Causes and Treatment of Wegener’s granulomatosisAlicia YuYifan (Emily) HuGrace TangJessica Wu

PHM142 October 20, 2015

PHM142 Fall 2015Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson

Case Study

A 45 year-old male goes to the physician, complaining of nasal congestion, cough, chest discomfort and dyspnea. He thinks it is just a common cold, but also reports finding bloody nasal discharge, and experiences painful swelling in his lower eyelid. The physician orders a blood and urine test.

Case Study: Laboratory Results

Blood Test shows:

❏Leukocytosis [Inflammation]

❏Elevated erythrocyte sedimentation rate [Inflammation]

❏C-reactive protein levels:50 mg/L [Inflammation]

❏ANCA positive (Anti-Neutrophil Cytoplasmic Antibodies) [Autoimmune response]

Urine Test

❏Elevated RBC components [Kidney disease]

What is Wegener’s Granulomatosis?❏ a.k.a. granulomatosis with polyangiitis (GPA).

❏ An uncommon systemic disorder that causes inflammation of blood vessels.

❏ This inflammation is accompanied by granuloma formation which restricts the supply of blood to various organs.

❏ GPA is characterized by an close association with ANCA (anti-neutrophil cytoplasm antibody) targeted against PR3 (proteinase 3).

❏ About 80-90% of patients with GPA are ANCA-positive.

❏ The levels of PR3-ANCA is highly specific for GPA and thus is a valuable tool for the diagnosis of this disease.

❏ Today, our knowledge pertaining the cause and pathogenesis of GPA are still incomplete. The clue to the initiating event in GPA is considered to be a combination of environmental and genetic factors.

Infected Organs and Symptoms❏ The major sites of infection usually involve the upper and lower respiratory tracts and

kidneys. The symptoms at these infected sites include:

recurrent infections of the nose

❏ sinus pain and inflammation

❏ mucosal thickening

❏ cough

❏ shortness of breath

❏ chest pain

❏ blood in urine

❏ During active disease, patient may have other non-specific symptoms such as weight loss, joint pain, skin sores, malaise, eye swelling, and some forms of hearing loss.

Diagnosis

❏ urinalysis ❏ measure renal function

❏ imaging studies❏ X-Rays, CT scans, MRI

❏ tissue abnormalities

no test specific for GPA

physical symptoms❏ non-specific: e.g. cold-like symptoms

❏ other symptoms: renal failures, ocular inflammations

❏ blood tests❏ positive for ANCA

❏ presence of PR3-ANCA

Pathogenesis

❏ Dual morphology - necrotizing vasculitis and extravascular granulomatous inflammation

❏ Usually starts as granulomatous disease before it converts to systemic autoimmune vasculitis

Hypotheses regarding the pathogenesis of GPA concentrate on PR3-ANCA, TNF-alpha, neutrophils, T and B cells in granuloma formation and induction of vasculitis.

Pathogenesis - proposed mechanismsSome in vitro and in vivo studies support the concept that PR3-ANCA and TNF-alpha interaction activate neutrophil granulocytes, thereby inducing subsequent endothelial damage in blood vessels and further leukocyte recruitment resulting in vasculitis.

Causes❏ Genetic Factors

❏ MHC:

❏ particularly HLDPB1*0401 - significant risk factor

❏ HLA-DPB4

❏ risk factor for GPA but not for other AAV (anca-associated vasulitis)

❏ Environmental Factors❏ infections

❏ bacterial: Staphylococcus aureus

❏ exposure to inhaled substances

❏ fume and particulate

❏ drugs

❏ evidence suggesting that some drugs may induce ANCA production

Treatment❏Cyclophosphamide (Trade name: Cytoxan)

❏ Anti-cancer and Immunosuppressant

❏Prednisone (Cortisone)

❏ Corticosteroid: prevents inflammation, immunosuppressive

❏Methotrexate (Trade name: Rheumatrex)

❏ Anti-cancer and immunosuppressant

❏Trimethoprim/sulfamethoxazole (Trade name: Bactrim)

❏ Antibiotics to prevent relapse

Treatment: Rituximab❏Trade Name: Rituxan

❏Chimeric monoclonal antibody that binds to CD20 protein, destroying B cells

❏IV administration, 10 mg/mL

❏Used in combination with glucocorticoids

❏Studies found it to be effective in adults patients with refractory GPA

❏Other uses: treatment of Non Hodgkin’s Lymphoma, and Rheumatoid Arthritis

Summary❏Wegener’s granulomatosis, a.k.a. granulomatosis with

polyangiitis (GPA), is an autoimmune disease characterized by granuloma formation-induced inflammation and necrotic vasculitis

❏Undefined etiology and pathogenesis ❏ Risk factors: genetic and environmental❏ Models of pathogenesis have been proposed

❏ inconclusive due to lack of supporting evidence

❏Pathological hallmark: presence of PR3-ANCA❏Treatment: immunosuppressants (eg. Cyclophosphamide,

Prednisone)❏Rituximab : Chimeric monoclonal antibody that binds to

CD20 protein to destroying B cells, found to be effective in refractory cases

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